This invention relates to novel compounds which are thyroid receptor ligands, and are preferably selective for the thyroid hormone receptor xcex2, and to methods of preparing such compounds and to methods for using such compounds such as in the regulation of metabolism.
While the extensive role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow. This has also limited the development of thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.
Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels, these hormones maintain body weight, the metabolic rate, body temperature, and mood, and influence serum low density lipoprotein (LDL) levels. Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of thyroid-stimulating hormone (TSH), thyroxine (3,5,3xe2x80x2,5xe2x80x2-tetraiodo-L-thyronine, or T4) and triiodothyronine (3,5,3xe2x80x2-triiodo-L-thyronine, or T3). However, replacement therapy, particularly in older individuals is limited by certain of the deleterious effects of thyroid hormones.
In addition, some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
Development of specific and selective thyroid hormone receptor agonists could lead to specific therapies for these common disorders while avoiding the cardiovascular and other toxicities of native thyroid hormones. Tissue-selective thyroid hormone agonists may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist and targeting receptor subtypes. Thyroid hormone receptor agonists that interact selectively with the xcex2-form of the thyroid hormone receptor offers an especially attractive method for avoiding cardio-toxicity.
Thyroid hormone receptors (TRs) are, like other nuclear receptors, single polypeptide chains. The various receptor forms appear to be products of two different genes xcex1 and xcex2. Further isoform differences are due to the fact that differential RNA processing results in at least two isoforms from each gene. The TRxcex11, TRxcex21 and TRxcex22, isoforms bind thyroid hormone and act as ligand-regulated transcription factors. In adults, the TRxcex21 isoform is the most prevalent form in most tissues, especially in the liver and muscle. The TRxcex12 isoform is prevalent in the pituitary and other parts of the central nervous system, does not bind thyroid hormones, and acts in many contexts as a transcriptional repressor. The TRxcex11 isoform is also widely distributed, although its levels are generally lower than those of the TRxcex21 isoform. This isoform may be especially important for development. Whereas many mutations in the TRxcex2 gene have been found and lead to the syndrome of generalized resistance to thyroid hormone, mutations leading to impaired TRxcex1 function have not been found.
A growing body of data suggest that many or most effects of thyroid hormones on the heart, and in particular on the heart rate and rhythm, are mediated through the xcex1-form of the TRxcex11 isoform, whereas most actions of the hormone such as on the liver, muscle and other tissues are mediated more through the xcex2-forms of the receptor. Thus, a TRxcex2-selective agonist might not elicit the cardiac rhythm and rate influences of the hormones but would elicit many other actions of the hormones. It is believed that the xcex1-form of the receptor is the major drive to heart rate for the following reasons:
1) tachycardia is very common in the syndrome of generalized resistance to thyroid hormone in which there are defective TRxcex2-forms, and high circulating levels of T4 and T3;
2) there was a tachycardia in the only described patient with a double deletion of the TRxcex2 gene (Takeda et al, J. Clin. Endrocrinol. and Metab. 1992, Vol. 74, p. 49);
3) a double knockout TRxcex1 gene (but not xcex2-gene) in the mouse has a slower pulse than control mice; and,
4) western blot analysis of human myocardial TRs show presence of the TRxcex11, TRxcex12 and TRxcex22 proteins, but not TRxcex21.
If these indications are correct, then a TRxcex2-selective agonist could be used to mimic a number of thyroid hormone actions, while having a lesser effect on the heart. Such a compound may be used for: (1) replacement therapy in elderly subjects with hypothyroidism who are at risk for cardiovascular complications; (2) replacement therapy in elderly subjects with subclinical hypothyroidism who are at risk for cardiovascular complications; (3) obesity; (4) hypercholesterolemia due to elevations of plasma LDL levels; (5) depression; and, (6) osteoporosis in combination with a bone resorption inhibitor.
In accordance with the present invention, compounds are provided which are thyroid receptor ligands, and have the general formula I: 
in which:
X is oxygen (xe2x80x94Oxe2x80x94), sulfur (xe2x80x94Sxe2x80x94), methylene(xe2x80x94CH2xe2x80x94), carbonyl (xe2x80x94COxe2x80x94), or xe2x80x94NHxe2x80x94;
Y is xe2x80x94(CH2)nxe2x80x94 where n is an integer from 1 to 5, or xe2x80x94Cxe2x95x90Cxe2x80x94 which may be cis or trans (also referred to as cis- or trans-ethylene);
R1 is halogen, trifluoromethyl, or alkyl of 1 to 6 carbons or cycloalkyl of 3 to 7 carbons;
R2 and R3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 6 carbons, at least one of R2 and R3 being other than hydrogen;
R4 is hydrogen or lower alkyl;
R5 is hydrogen or lower alkyl;
R6 is carboxylic acid, or an ester thereof (preferably an alkyl ester), or a prodrug thereof;
R7 is hydrogen or an alkanoyl or aroyl (such as acetyl or benzoyl) or other group capable of bioconversion to generate the free phenol structure (wherein R7=H);
including all stereoisomers thereof, prodrug esters thereof, and pharmaceutically acceptable salts thereof.
In addition, in accordance with the present invention, a method for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependent upon the expression of a T3 regulated gene is provided, wherein a compound of formula I is administered in a therapeutically effective amount. The compound of formula I is preferably an agonist that is preferably selective for the thyroid hormone receptor-beta. Examples of such diseases associated with metabolism dysfunction or are dependent upon the expression of a T3 regulated gene are set out hereinafter and include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucoma and congestive heart failure.